Most of the genes involved in the pathogenesis of the DNA replication and repair syndromes have now been cloned, and our understanding of the basis for the pleiotropic phenotype associated with many of these syndromes has rapidly and dramatically expanded. The elucidation of the specific interactions between
proteins that comprise the
transcription factor complex TFIIH raises the possibility that nucleotide excision repair,
RNA polymerase II transcription, and cell cycle control are connected. Defects in the XPB, XPD, and XPG genes can result in three different syndromes,
xeroderma pigmentosum,
Cockayne syndrome, or
trichothiodystrophy, depending on the specific mutation involved. The recent cloning of the genes involved in
Bloom syndrome (BLM) and
Werner syndrome (WRN) show that both are
DNA and
RNA helicases with homology to each other and to other DExH box helicases, yet the mechanism by which defects in these genes cause such different phenotypes is not yet understood. The
ataxia-telangiectasia gene (ATM) is involved in a variety of signal transduction pathways that regulate the cellular response to normal proliferative stimuli as well as the response to DNA damage, and the disruption of these signal transduction pathways provides an explanation for
ataxia-telangiectasia characteristics such as ionizing radiation sensitivity, immunodeficiency, and
infertility. Although the first
Fanconi anemia gene (FAC) was cloned over 5 years ago, and a second
Fanconi anemia gene (FAA) was cloned in 1996, the biochemical function of
Fanconi anemia proteins largely remains a mystery. The recent construction of mutant mouse strains for several of these diseases should help unlock the difficult puzzle of the pathogenesis of these syndromes.